John Theurer Cancer Center Investigators Contribute to Knowledge Base on Use of Selinexor in Multiple Myeloma (MM)

Review article and reports from STOMP and STORM trials further characterize role of novel selective inhibitor of nuclear export (SINE) in MM treatment

Investigators from Hackensack University Medical Center’s  John Theurer Cancer Center, a part of Georgetown Lombardi Comprehensive Cancer Center, are contributing to the growing knowledge base on the use of selinexor, a first-in-class, oral, selective inhibitor of nuclear export (SINE), in the treatment of multiple myeloma (MM), as reported in three recent publications. The publications, which include a review article and reports from two clinical trials, further characterize the efficacy, safety, and mechanism of action (MOA) of selinexor as well as its apparent impact on health-related quality of life (HRQOL) in patients with MM.

Multiple Myeloma is the second most common hematologic malignancy in the United States, accounting for roughly 2% of all diagnosed cancers and cancer-related deaths.1 An estimated 34,470 new cases of MM will be diagnosed in the U.S. in 2022, according to the American Cancer Society.2 Despite the recent introduction of numerous highly efficacious therapeutics for MM, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (MAbs), as well as combinations thereof, all patients eventually relapse, often with more aggressive and difficult-to-treat disease. Each relapse typically results in rapid development of “triple class-refractory” (PI, IMiD, MAb) MM, as well as the evolution of “penta-refractory” disease, which is characterized by resistance to the five most commonly employed anti-MM therapies including lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab (or isatuximab).

“The generally poor prognosis for patients with heavily pre-treated and resistant disease underscores the need for new therapeutic approaches in multiple myeloma,” said Noa Biran, M.D., associate professor of medicine at Hackensack Meridian School of Medicine and a practicing oncologist/hematologist in the Multiple Myeloma Division of John Theurer Cancer Center. “The availability of selinexor provides these patients with an orally administered therapeutic option with demonstrated safety and efficacy and a chance for clinically meaningful benefit. With its novel mechanism of action and promising results in clinical trials thus far, selinexor will likely contribute to further advancement of multiple myeloma therapy.”

In July 2019 the U.S. Food and Drug Administration (FDA) approved selinexor in combination with low-dose dexamethasone for the treatment of adult patients with relapsed/refractory MM (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two PIs, at least two IMiDs, and an anti-CD38 MAb. In December 2020 the FDA approved the once weekly XVd combination – selinexor, bortezomib, and dexamethasone – for patients with at least one prior therapy, confirming the clinical benefit of selinexor in previously treated MM; this was the first approval of a once-weekly bortezomib-based triplet for previously treated MM. Additionally, the National Comprehensive Cancer Network has added XVd, selinexor-pomalidomide-dexamethasone (XPd), and selinexor-daratumumab-dexamethasone (XDd) to its guidelines for the treatment of previously treated MM.3

Review article summarizes selinexor mechanism of action, efficacy and safety data from clinical trials

Dr. Biran and David Siegel, M.D., of John Theurer Cancer Center contributed to a review article, recently published in Expert Review of Hematology, that provides an overview of the selinexor MOA, as well as efficacy and safety data from clinical studies using selinexor for the treatment of MM. Selinexor works by inhibiting the nuclear export function of the protein exportin-1 (XPO1, also known as CRM1), resulting in the nuclear retention and functional reactivation of multiple tumor suppressor proteins (TSPs) and reduced translation of oncogenic messenger RNAs (mRNAs). The inhibitory action leads to cell death in cells with high levels of DNA damage, including many types of malignant cells, while largely sparing normal cells because they lack significant DNA damage. Reactivation of TSPs is thought to contribute substantially to apoptosis (programmed cell death) in cells with substantial DNA damage, including cancer cells.4

The review also summarizes data from the Selinexor Treatment of Refractory Melanoma (STORM), Selinexor and Backbone Treatments of Multiple Myeloma Patients (STOMP), and Bortezomib, Selinexor, and Dexamethasone (BOSTON) trials. These trials demonstrated safety and efficacy in patients with triple-class refractory as well as early relapsed MM.4

“Selinexor, with its unique and complementary actions, synergizes well with many agents commonly used in the treatment of multiple myeloma, particularly proteasome inhibitors, which also affect protein degradation in the cell,” stated Dr. Siegel, who is chief of the Myeloma Division at John Theurer Cancer Center. “Selinexor has demonstrated activity in patients who are heavily pretreated, patients with triple-, quad-, or penta-refractory disease, and those who are highly cytogenetic, suggesting it has the potential to reverse refractoriness to other agents and improve response rates.”

XKd combination demonstrates efficacy and safety in STOMP trial

Dr. Biran is co-author of a British Journal of Cancer article reporting results from the ongoing Phase 1b/2 STOMP trial, which is investigating the safety and efficacy of once-weekly therapy with the selinexor-dexamethasone-carfilzomib (XKd) combination in 32 patients with RRMM not refractory to carfilzomib. The regimen was highly effective and well-tolerated, with an overall response rate of 78%, including 14 patients (44%) with at least very good partial responses. Common treatment-related adverse events included thrombocytopenia, nausea, anemia, and fatigue, all of which were expected and manageable with supportive care and dose modifications. The investigators identified the maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all once weekly.5

“The high efficacy of XKd, as demonstrated thus far in the STOMP trial, is on par with that demonstrated by currently recommended triplet combinations that utilize carfilzomib and dexamethasone to treat patients with relapsed and refractory multiple myeloma,” Dr. Biran observed. “Moreover, the combination appears to be synergistic, as the 78% overall response rate far exceeds the roughly 30% overall response rate reported with single-agent selinexor therapy in patients who are very heavily refractory. The results suggest the XKd combination has the potential to ‘rescue’ refractoriness to these agents and improve response rates.”

STORM trial analysis shows no decline in HRQOL with selinexor + dexamethasone

Drs. Biran and Siegel were co-investigators in a quality-of-life analysis of 80 participants in the STORM trial, a Phase 2b, single-arm, open-label, multicenter study of selinexor with low-dose dexamethasone in patients with penta-exposed RRMM.  As reported in BMC Cancer, a majority of participants did not experience a decline in HRQOL based on minimal clinically important differences (the smallest meaningful improvement in the score of a patient-reported outcomes PRO domain, interpreted as a minimum level of perceived benefit by patients) during early cycles of treatment. Treatment responders experienced less decline in HRQOL from baseline to end of treatment than did non-responders; this finding was significant for the General version of the Functional Assessment of Cancer Therapy (FACT-G) instrument, but not for other measures.6 

“Thanks to the expanded portfolio of novel therapies in MM, patients live longer, and quality of life becomes especially important,” noted Andre Goy, M.D., M.S., chairman and executive director of John Theurer Cancer Center. “Selinexor being an oral agent, can not only greatly reduce the disease burden, through a new MOA, but also improve convenience, leading to better outcome and quality of life”.